The overall goal of the proposed studies is to understand how infection with influenza A virus inhibits disease progression in asthma. Our hypothesis is that infection with influenza A virus alters the pulmonary environment and enhances the development of protective immune responses to allergens inhaled 2-4 weeks after infection. We believe that infection with influenza virus can in some situations promote "protective" immunity by the altering dendritic cell (DC) function in, and the cellular composition of the lungs, in a way that enhances the development of regulatory/suppressor cells, which inhibit the pulmonary bias towards Th2 sensitization, and which inhibit the development of airway hyperreactivity (AHR), asthma exacerbations and disease progression. Our laboratory is well positioned to perform these studies, because we have examined allergen-induced AHR in mice for many years, and have acquired a large number of tools and reagents to study many parameters of airway inflammation. We have examined the role of pulmonary dendritic cells (DCs), including CD8alpha- and CD8alpha+ subsets of DCs, and antigen- specific CD4+ regulatory T cells in AHR, and have defined the parameters required for their development. In addition, we were the first to demonstrate a major role for NKT cells in the development of AHR, and have a large number of reagents to study NKT cells (CD1d tetramers, NKT cell deficient and NKT cell transgenic mice, and expertise to purify and adoptively transfer NKT cells). Finally, we have previously shown that infection with influenza A virus followed 2-4 wks later by respiratory exposure to allergen results in an immune response that protects against AHR. We now propose to examine how influenza A infection alters the function of pulmonary DCs, NKT cells and the development of regulatory T cells that inhibit AHR. Dr. Nicole Baumgarth, DVM, PhD, (University of California, Davis) has extensive experience in the study of influenza virus, and will assist us with these experiments. By understanding the specific mechanisms by which influenza affects the lung, we will develop a much greater understanding of immune responses that protect against Th2 inflammation and pulmonary exacerbations. We will also learn more about regulatory mechanisms that affect airway inflammation, and how viral infections and the environment affect the development of asthma.